Genetic Variant POLA2:p.Thr139Ser (chr11-65275952-A-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_002689.4(POLA2):c.415A>T(p.Thr139Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T139A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

POLA2
NM_002689.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.20

Publications

2 publications found

Variant links:

Genes affected

POLA2 (HGNC:30073): (DNA polymerase alpha 2, accessory subunit) Predicted to enable DNA binding activity. Involved in DNA replication, synthesis of RNA primer. Located in cytosol and nucleoplasm. Part of alpha DNA polymerase:primase complex. [provided by Alliance of Genome Resources, Apr 2022]

POLA2 Gene-Disease associations (from GenCC):

telomere syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

POLA2 links:

ENSG00000285816 (HGNC:):

ENSG00000285816 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.0585 (below the threshold of 3.09). Trascript score misZ: 1.5804 (below the threshold of 3.09). GenCC associations: The gene is linked to telomere syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.031416148).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002689.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLA2	NM_002689.4	MANE Select	c.415A>T	p.Thr139Ser	missense	Exon 5 of 18	NP_002680.2
POLA2	NM_001438747.1		c.415A>T	p.Thr139Ser	missense	Exon 5 of 18	NP_001425676.1
POLA2	NM_001437761.1		c.415A>T	p.Thr139Ser	missense	Exon 5 of 18	NP_001424690.1	A0A9L9PY44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLA2	ENST00000265465.8	TSL:1 MANE Select	c.415A>T	p.Thr139Ser	missense	Exon 5 of 18	ENSP00000265465.3	Q14181-1
ENSG00000285816	ENST00000649896.1		n.415A>T		non_coding_transcript_exon	Exon 5 of 20	ENSP00000498025.1	A0A3B3ITS5
POLA2	ENST00000525924.2	TSL:5	c.415A>T	p.Thr139Ser	missense	Exon 5 of 18	ENSP00000434173.2	H0YDR7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.0050

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.10

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.50

M_CAP

Benign

0.0053

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

PhyloP100

-1.2

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.30

REVEL

Benign

0.049

Sift

Benign

0.85

Sift4G

Benign

0.97

Polyphen

0.0

Vest4

0.20

MutPred

0.33

Loss of glycosylation at T139 (P = 0.0323)

MVP

0.40

MPC

0.16

ClinPred

0.042

GERP RS

-6.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over